U.S. patent application number 11/824245 was filed with the patent office on 2008-01-03 for synthesis of diethyl{[5-(3-fluorophenyl)-pyridine-2yl]methyl}phosphonate.
Invention is credited to Xiaoyong Fu, Tiruvettipuram K. Thiruvengadam, Jianguo Yin, Kelvin H. Yong, Ilia A. Zavialov.
Application Number | 20080004449 11/824245 |
Document ID | / |
Family ID | 38606711 |
Filed Date | 2008-01-03 |
United States Patent
Application |
20080004449 |
Kind Code |
A1 |
Yong; Kelvin H. ; et
al. |
January 3, 2008 |
Synthesis of
diethyl{[5-(3-fluorophenyl)-pyridine-2yl]methyl}phosphonate
Abstract
This application discloses a novel process for the preparation
of phosphonate esters useful as intermediates in the preparation of
himbacine analogs, themselves useful as thrombin receptor
antagonists. The chemistry taught herein can be exemplified by the
following scheme: ##STR1## wherein R.sup.9 is selected from alkyl,
aryl heteroaryl and arylalkyl groups having 1 to 10 carbon atoms,
and R.sup.11 is selected independently for each occurrence from
alkyl, aryl heteroaryl and arylalkyl groups having 1 to 10 carbon
atoms and hydrogen, X.sup.2 is Cl, Br, or I; X.sup.3 is selected
from Cl and Br; and PdL.sub.n is a supported palladium metal
catalyst or a soluble heterogeneous palladium catalyst. The
L-derivatizing reagent is a moiety which converts the alcohol
functional group of compound 137D to any leaving group which can be
displaced by a triorgano-phosphite phosphonating agent.
Inventors: |
Yong; Kelvin H.; (Lyndhurst,
NJ) ; Zavialov; Ilia A.; (Princeton, NJ) ;
Yin; Jianguo; (Plainsboro, NJ) ; Fu; Xiaoyong;
(Edison, NJ) ; Thiruvengadam; Tiruvettipuram K.;
(Kendall Park, NJ) |
Correspondence
Address: |
SCHERING-PLOUGH CORPORATION;PATENT DEPARTMENT (K-6-1, 1990)
2000 GALLOPING HILL ROAD
KENILWORTH
NJ
07033-0530
US
|
Family ID: |
38606711 |
Appl. No.: |
11/824245 |
Filed: |
June 29, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60817867 |
Jun 30, 2006 |
|
|
|
Current U.S.
Class: |
546/284.1 |
Current CPC
Class: |
A61P 43/00 20180101;
C07D 405/06 20130101; C07F 9/58 20130101; A61P 9/10 20180101; A61P
29/00 20180101; A61P 7/02 20180101 |
Class at
Publication: |
546/284.1 |
International
Class: |
C07D 405/02 20060101
C07D405/02 |
Claims
1. A process for making a compound having the structure of compound
11: ##STR28## wherein R1 is an alkyl group of from 1 to about 4
carbon atoms, the process comprising: (a) reacting
(5-halo-pyridin-2-yl)-methanol of the Formula 137A ##STR29## where
X.sup.2 is selected independently from Cl, Br, or I; with an
X.sup.1 halogenating agent, to produce a compound of the formula of
compound 137, ##STR30## where X.sup.1 is the same for each
occurrence and is selected from Cl or Br and X.sup.2 is as defined
above; (b) reacting compound 137 with a phosphite compound of the
structure of Formula A: ##STR31## wherein R.sup.9 is selected from
alkyl, aryl, heteroaryl, and arylalkyl groups having 1 to 10 carbon
atoms, to produce compound 138: ##STR32## wherein R.sup.9 is as
defined above; (c) treating compound 138 with HX.sup.3 , where
X.sup.3 is selected from Cl and Br, to precipitate the
corresponding hydrohalide salt of Formula 138 A ##STR33## (d)
reacting the hydrohalide salt from step "c" with a
3-flurophenylboronate compound of the structure of Formula B
##STR34## wherein R.sup.11 is selected independently for each
occurrence from alkyl, aryl heteroaryl and arylalkyl groups having
1 to 10 carbon atoms and hydrogen, optionally in the presence of a
palladium catalyst to produce compound 116.
2. A process for making a compound having the structure of compound
11: ##STR35## wherein R1 is an alkyl group of from 1 to about 4
carbon atoms, the process comprising: (a) reacting
(5-Bromo-2-methoxy-pyridine) with a chlorinating agent selected
from OSCl.sub.2, PCl.sub.3, PCl.sub.5, to produce a compound of the
formula of compound 137. ##STR36## (b) reacting compound 137 with a
phosphite compound of the structure of Formula A ##STR37## to
produce compound 138 ##STR38## wherein R.sup.9 is separately
selected for each occurrence from alkyl, aryl, heteroaryl, and
arylalkyl groups having 1 to 10 carbon atoms; (c) treating compound
138 with HCl to obtain the corresponding hydrochloride salt; (d)
reacting the hydrochloride salt from step "c" with
3-flurophenylboronic acid, optionally in the presence of a
palladium catalyst to produce compound having the structure of
compounds 16, ##STR39## (e) reacting the compound 116 formed in
step "d" with a compound of the structure of compound 15, ##STR40##
to yield compound 11.
3. The process of claim 2 wherein the phosphite compound used in
step "b" is a trialkyl phosphate.
4. The process of claim 2 wherein the phosphite used in step "b" is
triethyl phosphite.
5. A process for making a compound of the structure of compound 116
##STR41## wherein R.sup.9 is separately selected for each
occurrence from alkyl, aryl, heteroaryl, and arylalkyl groups
having 1 to 10 carbon atoms, the process comprising: reacting a
hydrochloride salt compound having the structure of compound 139,
where R.sup.9 is as defined above, ##STR42## with
3-flurophenylboronic acid in the presence of a palladium
catalyst.
6. The process of claim 5 wherein compound 139 is provided by (a)
reacting the hydrochloride salt of the structure of compound 137
##STR43## with a phosphite compound of the structure of Formula A
##STR44## wherein R.sup.9 is separately selected for each
occurrence from alkyl, aryl, heteroaryl, and arylalkyl groups
having 1 to 10 carbon atoms; and (b) treating the reaction product
from step "a" with HCl to obtain compound 139.
7. The process of claim 6 wherein the phosphite compound used in
step "a" is a trialkyl phosphite.
8. The process of claim 7 wherein the trialkyl phosphite used in
step "a" is triethyl phosphite.
9. The process of claim 5 further comprising after the "treating"
step "b", the step of precipitating the phosphonate hydrochloride
formed in step "b" by adding an antisolvent to the reaction mixture
containing the phosphonate hydrochloride compound of structure
139.
10. The process of claim 1 wherein said palladium catalyst is
palladium metal supported on carbon black.
11. The process of claim 1 wherein said palladium catalyst is a
soluble palladium catalyst.
12. A process for making a compound of the structure of compound
116 ##STR45## wherein R.sup.9 is separately selected for each
occurrence from alkyl, aryl, heteroaryl, and arylalkyl groups
having 1 to 10 carbon atoms, the process comprising: (a) reacting
(5-halo-pyridin-2-yl)-methanol of the Formula 137A ##STR46## where
X.sup.2 is selected independently from Cl, Br, or I; with an
X.sup.1 halogenating agent, to produce a compound of the formula of
compound 137, ##STR47## where X.sup.1 is the same for each
occurrence and is selected from Cl or Br and X.sup.2 is as defined
above; (b) reacting compound 137 with a phosphite compound of the
structure of Formula A, ##STR48## wherein R.sup.9 is selected from
alkyl, aryl, heteroaryl, and arylalkyl groups having 1 to 10 carbon
atoms, to produce compound 138, ##STR49## wherein R.sup.9 is as
defined above; (c) treating compound 138 with HX.sup.3 , where
X.sup.3 is selected from Cl and Br, to precipitate the
corresponding hydrohalide salt of Formula 138A, ##STR50## wherein
R.sup.9 is as defined above; and (d) reacting the hydrohalide salt
from step "c" with a 3-flurophenylboronate compound of the
structure of Formula B ##STR51## wherein R.sup.11 is selected
independently for each occurrence from alkyl, aryl heteroaryl and
arylalkyl groups having 1 to 10 carbon atoms and hydrogen,
optionally in the presence of a palladium catalyst to produce
compound 116.
13. A process for making a compound of the structure of compound
116 ##STR52## wherein R.sup.9 is separately selected for each
occurrence from alkyl, aryl, heteroaryl, and arylalkyl groups
having 1 to 10 carbon atoms, the process comprising: (a) reacting
(5-halo-pyridin-2-yl)-methanol of the Formula 137A ##STR53## where
X.sup.2 is selected independently from Cl, Br, or 1, with an
X.sup.1 halogenating agent, to produce a compound of the formula of
compound 137, ##STR54## where X.sup.1 is the same for each
occurrence and is selected from Cl or Br and X.sup.2 is as defined
above; (b) reacting compound 137 with a phosphite compound of the
structure of Formula A, ##STR55## wherein R.sup.9 is selected from
alkyl, aryl, heteroaryl, and arylalkyl groups having 1 to 10 carbon
atoms, to produce compound 138, ##STR56## wherein R.sup.9 is as
defined above; (c) treating compound 138 with HX.sup.3 , where
X.sup.3 is selected from Cl and Br, to precipitate the
corresponding hydrohalide salt of Formula 138A, ##STR57## wherein
R.sup.9 is as defined above; and (d) reacting the hydrohalide salt
from step "c" with an organometallic compound capable of displacing
X.sup.2 of Formula 138A with a 3-flurophenyl moiety of Formula B',
##STR58## to produce compound 116.
14. The process of claim 13 wherein the organometallic compound
used in step "d" is selected from the group consisting of:
fluoroaryl-alkylboranes; fluoroaryl-haloboranes; and fluoroaryl-
zinc, -aluminium, -magnesium, and -tin reagents.
15. The process of claim 1 wherein the phosphite used in step "b"
is triethyl phosphite.
16. The process of claim 2 wherein said palladium catalyst is
selected from palladium metal supported on carbon black and a
soluble palladium catalyst.
17. The process of claim 3 wherein said palladium catalyst is
selected from palladium metal supported on carbon black and a
soluble palladium catalyst.
18. The process of claim 4 wherein said palladium catalyst is
selected from palladium metal supported on carbon black and a
soluble palladium catalyst.
19. The process of claim 5 wherein said palladium catalyst is
selected from palladium metal supported on carbon black and a
soluble palladium catalyst.
20. The process of claim 6 wherein said palladium catalyst is
selected from palladium metal supported on carbon black and a
soluble palladium catalyst.
21. The process of claim 7 wherein said palladium catalyst is
selected from palladium metal supported on carbon black and a
soluble palladium catalyst.
22. The process of claim 8 wherein said palladium catalyst is
selected from palladium metal supported on carbon black and a
soluble palladium catalyst.
23. The process of claim 9 wherein said palladium catalyst is
selected from palladium metal supported on carbon black and a
soluble palladium catalyst.
24. The process claim 5 further comprising after the "treating"
step "b", the step of precipitating the phosphonate hydrochloride
formed in step "b" by adding an antisolvent to the reaction mixture
containing the phosphonate hydrochloride compound of structure
139.
25. The process claim 6 further comprising after the "treating"
step "b", the step of precipitating the phosphonate hydrochloride
formed in step "b" by adding an antisolvent to the reaction mixture
containing the phosphonate hydrochloride compound of structure
139.
26. The process claim 7 further comprising after the "treating"
step "b", the step of precipitating the phosphonate hydrochloride
formed in step "b" by adding an antisolvent to the reaction mixture
containing the phosphonate hydrochloride compound of structure
139.
27. The process claim 8 further comprising after the "treating"
step "b", the step of precipitating the phosphonate hydrochloride
formed in step "b" by adding an antisolvent to the reaction mixture
containing the phosphonate hydrochloride compound of structure 139.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is based on and claims the priority of U.S.
Provisional Application No. 60/817867 filed Jun. 30, 2006, which is
incorporated by reference herein in its entirety.
FIELD OF THE INVENTION
[0002] This application discloses a novel process in the
preparation of dialkyl{[5-(3-fluorophenyl)-pyridine-2-yl]alkyl}
phosphonate compounds which are useful in the synthesis of
himbacine analogs, themselves useful as thrombin receptor
antagonists.
BACKGROUND OF THE INVENTION
[0003] As described in copending U.S. patent application Ser. No.
11/331,324, filed Jan. 12, 2006 (herein, "the '324 application"),
the disclosure of which is incorporated herein in its entirety by
reference, himbacine analogs are useful as thrombin receptor
antagonists. Thrombin is known to have a variety of activities in
different cell types. Thrombin receptors are known to be present in
such diverse cell types as human platelets, vascular smooth muscle
cells, endothelial cells, and fibroblasts. Thrombin receptor
antagonists may be useful in the treatment of thrombotic,
inflammatory, atherosclerotic and fibroproliferative disorders, as
well as other disorders in which thrombin and its receptor play a
pathological role, for example, as described in U.S. Pat. No.
6,063,847, the disclosure of which is incorporated by reference.
Additional examples of thrombin receptor antagonists useful in the
treatment of thrombotic, inflammatory, atherosclerotic, and
fibroproliferative disorders, and the synthesis of these compounds,
are described in published U.S. Patent Application No. 2003/0216437
(herein, "the '437 publication"), the disclosure of which is
incorporated herein in its entirety by reference.
[0004] One thrombin receptor antagonist identified is an orally
bioavailable compound derived from himbacine having the structure
of the compound 11: ##STR2## Processes for the synthesis of this
and similar himbacine analog thrombin receptor antagonists are
disclosed in U.S. Pat. No. 6,063,847, and U.S. publication no.
2003/0216437, methods of using thrombin receptor antagonists are
disclosed in U.S. publication no. 2004/0192753, and the synthesis
of the bisulfate salt of a particular himbacine analog is disclosed
in U.S. publication no. 2004/0176418, the disclosures of which are
incorporated by reference herein.
[0005] As described in the '324 application mentioned herein above,
compound 11 may be synthesized from Compound 15: ##STR3## by
treatment with compound 16 in accordance with Scheme I.
##STR4##
[0006] Compound 15 is in turn prepared from compound 1: ##STR5##
wherein R.sub.5 and R.sub.6 are each independently selected from
the group consisting of H, alkyl, alkenyl, alkynyl, alkoxy,
cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups, in
four steps in accordance with the synthesis scheme shown in the
copending '324 application, which synthetic schemes are
incorporated herein by reference.
[0007] The copending '324 application describes the preparation of
compound 16 in accordance with Scheme II, below. ##STR6## With
reference to Scheme II, L is a leaving group selected from
halogens, esters, sulfonates and phosphates, R.sup.9 is selected
from alkyl, aryl heteroaryl and arylalkyl groups having 1 to 10
carbon atoms, and R.sup.11 is selected from alkyl, aryl heteroaryl
and arylalkyl groups having 1 to 10 carbon atoms and hydrogen. As
described in the '324 application, in the scheme for preparation of
compound 16, compound 36 is converted to compound 37 by first
treatment with sodium carbonate to liberate the pyridyl alcohol
free base, and the alcohol is subsequently reacted to convert the
hydroxyl group to a leaving group (L) which can be displaced by a
phosphite reagent to form the corresponding phosphonate ester.
Accordingly, as described in the '324 application, preferably
compound 37 is prepared by heating a solution of the alcohol
intermediate isolated from compound 36 with a reagent that converts
the hydroxyl functional group to a leaving group which can be
displaced by a diorgano-phosphite compound. Preferably, L is a
halogen, preferably Cl, and is preferably prepared by treating the
alcohol with a halogenation reagent, for example, PBr.sub.3,
PCl.sub.3, PCl.sub.5, and thionyl chloride, preferably thionyl
chloride, followed by quenching the reaction with sodium carbonate,
and extracting the product into toluene.
[0008] Compound 37 contained in the toluene extract is converted to
compound 38 by reacting a solution of compound 37 with a
diorgano-phosphite in the presence of a strong base, for example, a
metal alkyl, for example, lithium alkyl and a metal amide, for
example lithium bis(trimethylsilyl) amide.
[0009] The conversion of compound 38 to compound 16 is done by
reacting compound 38 with boronate, the reaction catalyzed by a
palladium catalyst. The catalyst used can be a homogeneous
catalyst, for example, a palladium phosphine, for example,
palladium tristriphenyl phosphine, and palladium
tris-ortho-tolyphosphine, and amine catalysts, for example,
bispalladium-trisbipyridine, or a heterogeneous catalyst, for
example, palladium supported on carbon black.
[0010] The scheme presented in the '345 application for the
synthesis of compound 16, a critical intermediate in the
preparation of a variety of thrombin receptor antagonists, requires
isolation or extraction of intermediates in two of the four steps,
and utilizes in one step a powerful base and a water sensitive
diorgano-phosphite compound. Moreover, the step shown in Scheme II
of reacting unisolated compound 38 with boronate to form compound
16 proved to provide variable results, rendering the process of
Scheme II undesirable for use in the preparation of commercial
quantities of material.
OBJECTIVES
[0011] In view of the foregoing, what is needed is a synthetic
scheme useful for preparing compounds critical to the preparation
of thrombin receptor antagonists. Particularly needed is a
synthetic scheme which utilizes safer materials and provides
reaction steps and processes affording practical scale up to a
batch size suitable for commercial scale preparation and requires
minimal equipment for isolation and purification of intermediates
and products and improved product yield. These and other objectives
and/or advantages are provided by the present invention.
SUMMARY OF THE INVENTION
[0012] In one embodiment, the present invention is a novel, simple
process of making dialkyl{[5-(3-fluorophenyl)-pyridine-2-yl]methyl}
phosphonate compounds (compounds having the structure of compound
116) which are useful in the synthesis of himbacine analogs that
have utility as thrombin receptor antagonist compounds: ##STR7##
wherein R.sup.9 is selected from alkyl, aryl, heteroaryl, and
arylalkyl groups having 1 to 10 carbon atoms, the process
comprising:
[0013] (a) reacting (5-halo-pyridin-2-yl)-methanol of the Formula
137A ##STR8## with an X.sup.1 halogenating agent, to produce a
compound of the formula of compound 137, ##STR9## where X.sup.1 is
the same for each occurrence and is selected from Cl or Br and
X.sup.2 is selected independently from Cl, Br, or I;
[0014] (b) reacting compound 137 with a phosphite compound of the
structure of Formula A ##STR10## to produce compound 138 ##STR11##
wherein R.sup.9 is as defined above;
[0015] (c) treating compound 138 with HX.sup.3 , where X.sup.3 is
selected from Cl and Br, to precipitate the corresponding
hydrohalide salt of Formula 138 A ##STR12##
[0016] (d) reacting the hydrohalide salt from step "c" with a
3-flurophenylboronate compound of the structure of Formula B
##STR13## wherein R.sup.11 is selected independently for each
occurrence from alkyl, aryl heteroaryl and arylalkyl groups having
1 to 10 carbon atoms and hydrogen, optionally in the presence of a
palladium catalyst to produce compound 116.
[0017] Preferably, the halogenating agent used in step "c" is
selected from a chlorinating agent (therefore X.sup.1 is Cl) or a
brominating agent (therefore X.sup.1 is Br) selected from
OSCl.sub.2, PCl.sub.3, PCl.sub.5, POCl.sub.3, O.sub.2SCl.sub.2,
(OCCl).sub.2, OSBr.sub.2, PBr.sub.3, PBr.sub.5, POBr.sub.3,
O.sub.2SBr.sub.2, (OCBr).sub.2, more preferably the halogenating
agent is thionyl chloride (therefore X.sup.1 is Cl). Preferably,
the phosphite compound used in step "b" is a trialkyl phosphite,
more preferably, triethyl phosphite. Preferably the boronate
compound used in step "d" is 3-fluoro-phenyl-boronic acid. When a
catalyst is used in the reaction of step "d", preferably the
catalyst is palladium supported on carbon black. Preferably, a
catalyst is used in step "d".
[0018] In some embodiments of the present invention, the method of
the present invention for the preparation of a compound of the
structure of compound 116 is part of a larger reaction scheme for
the preparation of a thrombin receptor antagonist having the
structure of compound 11, as shown below in Scheme III. ##STR14##
wherein the halogenating agent is selected from a chlorinating
agent (X.sup.1 is Cl) selected from OSCl.sub.2, PCl.sub.3,
PCl.sub.5, POCl.sub.3, O.sub.2SCl.sub.2, (OCCl).sub.2, and a
brominating (X.sup.1 is Br) selected from OSBr.sub.2, PBr.sub.3,
PBr.sub.5, POBr.sub.3, O.sub.2SBr.sub.2, (OCBr).sub.2; X.sup.1 is
the same for each occurrence and is selected, based on the
halogenating agent chosen, from Cl or Br; X.sup.2 is Cl, Br, or I;
X.sup.3 is selected from Cl and Br; R.sup.1 is a linear, branched
or cyclic alkyl, preferably having from 1 to about 4 carbon atoms,
more preferably C.sub.2H.sub.5--; R.sup.9 is selected from alkyl,
aryl, heteroaryl, and arylalkyl groups having 1 to 10 carbon atoms;
and R.sup.11 is selected independently for each occurrence from
alkyl, aryl heteroaryl and arylalkyl groups having 1 to 10 carbon
atoms and hydrogen. In some embodiments, the halogenating agent is
preferably thionyl chloride, X.sup.1 and X.sup.3 are preferably Cl
and X.sup.2 is preferably Br. In some embodiments R9 is preferably
C.sub.2H.sub.5--. In some embodiments the phosphite compound used
is preferably a trialkyl phosphite, more preferably, triethyl
phosphite. Preferably the boronate compound used is
3-fluoro-phenyl-boronic acid.
[0019] These and other aspects and advantages of the invention will
be apparent from the following description.
DETAILED DESCRIPTION OF THE INVENTION
[0020] The following definitions and terms are used herein or are
otherwise known to a skilled artisan. Except where stated
otherwise, the definitions apply throughout the specification and
claims. Chemical names, common names and chemical structures may be
used interchangeably to describe the same structure. These
definitions apply regardless of whether a term is used by itself or
in combination with other terms, unless otherwise indicated. Hence,
the definition of "alkyl" applies to "alkyl" as well as the "alkyl"
portions of "hydroxyalkyl," "haloalkyl," "alkoxy," etc.
[0021] Unless otherwise known, stated or shown to be to the
contrary, the point of attachment for a multiple term substituent
(two or more terms that are combined to identify a single moiety)
to a subject structure is through the last named term of the
multiple term substituent. For example, a cycloalkylalkyl
substituent attaches to a targeted structure through the latter
"alkyl" portion of the substituent (e.g.,
structure-alkyl-cycloalkyl).
[0022] The identity of each variable appearing more than once in a
formula may be independently selected from the definition for that
variable, unless otherwise indicated.
[0023] Unless stated, shown or otherwise known to be the contrary,
all atoms illustrated in chemical formulas for covalent compounds
possess normal valencies. Thus, hydrogen atoms, double bonds,
triple bonds and ring structures need not be expressly depicted in
a general chemical formula.
[0024] Double bonds, where appropriate, may be represented by the
presence of parentheses around an atom in a chemical formula. For
example, a carbonyl functionality, --CO--, may also be represented
in a chemical formula by --C(O)--, or --C(.dbd.O)--. One skilled in
the art will be able to determine the presence or absence of double
(and triple bonds) in a covalently-bonded molecule. For instance,
it is readily recognized that a carboxyl functionality may be
equivalently represented by --COOH, --C(O)OH, --C(.dbd.O)OH or
--CO.sub.2H.
[0025] The term "heteroatom," as used herein, means a nitrogen,
sulfur or oxygen atom. Multiple heteroatoms in the same group may
be the same or different.
[0026] As used herein, the term "alkyl" means an aliphatic
hydrocarbon group that can be straight or branched and comprises 1
to about 24 carbon atoms in the chain. Preferred alkyl groups
comprise 1 to about 15 carbon atoms in the chain. More preferred
alkyl groups comprise 1 to about 6 carbon atoms in the chain.
"Lower alkyl" means alkyl groups of 1 to 6 carbon atoms in the
chain. "Branched" means that one or more lower alkyl groups such as
methyl, ethyl or propyl, are attached to a linear alkyl chain. The
alkyl can be substituted by one or more substituents independently
selected from the group consisting of halo, aryl, cycloalkyl,
cyano, hydroxy, alkoxy, alkylthio, amino, --NH(alkyl),
--NH(cycloalkyl), --N(alkyl).sub.2 (which alkyls can be the same or
different), carboxy and --C(O)O-alkyl. Non-limiting examples of
suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl,
n-butyl, t-butyl, n-pentyl, heptyl, nonyl, decyl, fluoromethyl,
trifluoromethyl and cyclopropylmethyl.
[0027] "Alkenyl" means an aliphatic hydrocarbon group (straight or
branched carbon chain) comprising one or more double bonds in the
chain and which can be conjugated or unconjugated. Useful alkenyl
groups can comprise 2 to about 15 carbon atoms in the chain,
preferably 2 to about 12 carbon atoms in the chain, and more
preferably 2 to about 6 carbon atoms in the chain. The alkenyl
group can be substituted by one or more substituents independently
selected from the group consisting of halo, alkyl, aryl,
cycloalkyl, cyano and alkoxy. Non-limiting examples of suitable
alkenyl groups include ethenyl, propenyl, n-butenyl,
3-methylbut-enyl and n-pentenyl.
[0028] Where an alkyl or alkenyl chain joins two other variables
and is therefore bivalent, the terms alkylene and alkenylene,
respectively, are used.
[0029] "Alkoxy" means an alkyl-O-- group in which the alkyl group
is as previously described. Useful alkoxy groups can comprise 1 to
about 12 carbon atoms, preferably 1 to about 6 carbon atoms.
Non-limiting examples of suitable alkoxy groups include methoxy,
ethoxy and isopropoxy. The alkyl group of the alkoxy is linked to
an adjacent moiety through the ether oxygen.
[0030] The term "cycloalkyl" as used herein, means an unsubstituted
or substituted, saturated, stable, non-aromatic,
chemically-feasible carbocyclic ring having preferably from three
to fifteen carbon atoms, more preferably, from three to eight
carbon atoms. The cycloalkyl carbon ring radical is saturated and
may be fused, for example, benzofused, with one to two cycloalkyl,
aromatic, heterocyclic or heteroaromatic rings. The cycloalkyl may
be attached at any endocyclic carbon atom that results in a stable
structure. Preferred carbocyclic rings have from five to six
carbons. Examples of cycloalkyl radicals include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or the like.
[0031] "Alkynyl" means an aliphatic hydrocarbon group comprising at
least one carbon-carbon triple bond and which may be straight or
branched and comprising about 2 to about 15 carbon atoms in the
chain. Preferred alkynyl groups have about 2 to about 10 carbon
atoms in the chain; and more preferably about 2 to about 6 carbon
atoms in the chain. Branched means that one or more lower alkyl
groups such as methyl, ethyl or propyl, are attached to a linear
alkynyl chain. Non-limiting examples of suitable alkynyl groups
include ethynyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl,
and decynyl. The alkynyl group may be substituted by one or more
substituents which may be the same or different, each substituent
being independently selected from the group consisting of alkyl,
aryl and cycloalkyl.
[0032] The term "aryl," as used herein, means a substituted or
unsubstituted, aromatic, mono- or bicyclic, chemically-feasible
carbocyclic ring system having from one to two aromatic rings. The
aryl moiety will generally have from 6 to 14 carbon atoms with all
available substitutable carbon atoms of the aryl moiety being
intended as possible points of attachment. Representative examples
include phenyl, tolyl, xylyl, cumenyl, naphthyl,
tetrahydronaphthyl, indanyl, indenyl, or the like. If desired, the
carbocyclic moiety can be substituted with from one to five,
preferably, one to three, moieties, such as mono- through
pentahalo, alkyl, trifluoromethyl, phenyl, hydroxy, alkoxy,
phenoxy, amino, monoalkylamino, dialkylamino, or the like.
[0033] "Heteroaryl" means a monocyclic or multicyclic aromatic ring
system of about 5 to about 14 ring atoms, preferably about 5 to
about 10 ring atoms, in which one or more of the atoms in the ring
system is/are atoms other than carbon, for example nitrogen, oxygen
or sulfur. Mono- and polycyclic (e.g., bicyclic) heteroaryl groups
can be unsubstituted or substituted with a plurality of
substituents, preferably, one to five substituents, more
preferably, one, two or three substituents (e.g., mono- through
pentahalo, alkyl, trifluoromethyl, phenyl, hydroxy, alkoxy,
phenoxy, amino, monoalkylamino, dialkylamino, or the like).
Typically, a heteroaryl group represents a chemically-feasible
cyclic group of five or six atoms, or a chemically-feasible
bicyclic group of nine or ten atoms, at least one of which is
carbon, and having at least one oxygen, sulfur or nitrogen atom
interrupting a carbocyclic ring having a sufficient number of pi
(.pi.) electrons to provide aromatic character. Representative
heteroaryl (heteroaromatic) groups are pyridinyl, pyrimidinyl,
pyrazinyl, pyridazinyl, furanyl, benzofuranyl, thienyl,
benzothienyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl,
triazolyl, isothiazolyl, benzothiazolyl, benzoxazolyl, oxazolyl,
pyrrolyl, isoxazolyl, 1,3,5-triazinyl and indolyl groups.
[0034] The term "heterocyclic ring" or "heterocycle," as used
herein, means an unsubstituted or substituted, saturated,
unsaturated or aromatic, chemically-feasible ring, comprised of
carbon atoms and one or more heteroatoms in the ring. Heterocyclic
rings may be monocyclic or polycyclic. Monocyclic rings preferably
contain from three to eight atoms in the ring structure, more
preferably, five to seven atoms. Polycyclic ring systems consisting
of two rings preferably contain from six to sixteen atoms, most
preferably, ten to twelve atoms. Polycyclic ring systems consisting
of three rings contain preferably from thirteen to seventeen atoms,
more preferably, fourteen or fifteen atoms. Each heterocyclic ring
has at least one heteroatom. Unless otherwise stated, the
heteroatoms may each be independently selected from the group
consisting of nitrogen, sulfur and oxygen atoms.
[0035] The terms "Hal," "halo," "halogen" and "halide," as used
herein, mean a chloro, bromo, fluoro or iodo atom radical.
Chlorides, bromides and fluorides are preferred halides.
[0036] The term "carbonate", as used herein, is understood to
include bicarbonates.
[0037] The term "isomer", as used herein, is understood to mean one
of two or more molecules having the same number and kind of atoms
and hence the same molecular weight, but differing in respect to
the arrangement or configuration of the atoms.
[0038] The term "epimerizing", as used herein, is understood to
mean converting from one isomer to another, wherein it is the
relative position of an attached H that differs between the two
isomers.
[0039] The term "precipitate", as used herein, is understood to
mean to fall out of solution as a solid. Precipitation applies
equally to the formation of an insoluble salt "in situ", or
changing the solubility properties of a solvent. Examples of
changing the solubility properties of a solvent include cooling the
solution and the addition of a sufficient amount of an
"anti-solvent" to a solution such that precipitated compound has
reduced solubility in the combined solvents.
[0040] The term "dynamic resolution", as used herein, is understood
to mean a process in which a conversion from a first isomer to a
second isomer of the same compound in a solution is
thermodynamically driven by the depletion of the second isomer from
the solution by precipitation of the second isomer.
[0041] The following abbreviations are defined: EtOH is ethanol; Me
is methyl; Et is ethyl; Bu is butyl; n-Bu is normal-butyl, t-Bu is
tert-butyl, OAc is acetate; KOt-Bu is potassium tert-butoxide; NBS
is N-bromo succinimide; NMP is 1-methyl-2-pyrrolidinone; DMAP is
4-dimethylaminopyridine; THF is tetrahydrofuran; DBU is
1,8-diazabicyclo[5,4,0]undec-7-ene; DMA is N,N-dimethylacetamide;
n-BU.sub.4NBr is tetrabutylammonium bromide; n-Bu.sub.4NOH is
tetrabutylammonium hydroxide, n-Bu.sub.4NH.sub.2SO.sub.4 is
tetrabutylammonium hydrogen sulfate, and "equiv." or "eq." means
equivalents.
[0042] The term "n", as it is used herein, is understood to be an
integer having a value that is inclusive of the range recited
thereafter. Thus "n is between 0 and 4" and "n ranges 0-4" both
mean that n may have any of the values 0, 1, 2, 3 or 4.
[0043] As mentioned above, copending U.S. patent application Ser.
No. 11/331,324 (herein, "the '324 application") describes the
synthesis of compounds of the structure of compound 11 which have
promising activity as thrombin receptor inhibitors. ##STR15## As
illustrated below in Schemes IV and V, the '324 application
describes in detail the synthesis of compound 11 and related
compounds, which synthesis is incorporated herein by reference.
##STR16## ##STR17## ##STR18## ##STR19## A critical intermediate in
the synthesis of compound 11 are compounds having the structure of
compound 16 and related phoshonate esters (herein, sometimes
referred to for convenience as the compounds having the structure
of compound 116). The inventors have surprisingly discovered a
process for the synthesis of the compounds having the structure of
compound 116 which uses less active reagents and simplifies unit
operations in each synthetic step over a process for the
preparation of compounds having the structure of compound 116
described in the '324 application. In particular, improvements in
yield, specificity, and product purity are realized by isolation of
5-halo-pyridin-2-yl-methyl phosphonate ester (139), and by
selection of a triorganophosphite phosphonating agent in the
conversion of compound 137 to compound 138. Moreover, utilizing
these process steps, the current invention process results in a
greater overall yield of compounds having the structure of compound
116 based on the starting pyridyl alcohol, 75% overall yield for
the process of the present invention compared with an overall yield
of 60% for the process described in the '324 application.
[0044] The overall reaction scheme of the present invention is
schematically depicted in Scheme VI. ##STR20## wherein R.sup.9 is
selected from alkyl, aryl heteroaryl and arylalkyl groups having 1
to 10 carbon atoms, and R.sup.11 is selected independently for each
occurrence from alkyl, aryl heteroaryl and arylalkyl groups having
1 to 10 carbon atoms and hydrogen, X.sup.2 is Cl, Br, or I; X.sup.3
is selected from Cl and Br; and PdL.sub.n is a supported palladium
metal catalyst or a soluble heterogeneous palladium catalyst. The
L-derivatizing reagent can be a halogenating agent (thus L is a
halogen), for example, a chlorinating agent, for example,
OSCl.sub.2, PCl.sub.3, PCl.sub.5, POCl.sub.3, O.sub.2SCl.sub.2,
(OCCl).sub.2 (thus L is Cl), and a brominating agent, for example
OSBr.sub.2, PBr.sub.3, PBr.sub.5, POBr.sub.3, O.sub.2SBr.sub.2,
(OCBr).sub.2 (thus, L is Br). As will be appreciated, the
L-derivatizing reagent can also be a moiety which converts the
alcohol functional group to any leaving group which can be
displaced by the phosphonating agent (triorgano-phosphite) used to
covert compound 137D to compound 138D, for example a sulfonylester
(provided by, for example, benzensulfonyl chloride L-derivatizing
reagent), a sulfonate ester, and the L-derivatizing reagents
described in the copending '324 application, (incorporated herein
by reference).
[0045] Although all steps of Reaction Scheme VI can be carried out
individually, and the intermediate prepared in each phase isolated,
it is advantageous in the present reaction scheme to utilize
intermediate compound 137 "in situ" in the reaction medium obtained
after workup for use in the next step, the conversion from the
halide to the phosphonate (compound 138).
[0046] Each step of reaction Scheme VI will be discussed next.
[0047] The first step of the process of the invention is conversion
of a pyridyl hydroxyalkyl to the correspondind phosphono-alkyl.
This is illustrated in Scheme VI as the first step, conversion of
compound 136 to compounds of the structure 138. In the first step
of Scheme VI, the alcohol functional group of
[(5-(halo)-2-hydroxymethyl]-pyridine, where "halo" is selected from
bromine, chlorine and iodine, is reacted in solution with an
L-derivatizing reagent, as mentioned above, for example, a
chlorinating agent, for example OSCl.sub.2, PCl.sub.3, PCl.sub.5,
POCl.sub.3, O.sub.2SCl.sub.2, (OCCl).sub.2 (thus L is Cl), a
brominating agent, for example OSBr.sub.2, PBr.sub.3, PBr.sub.5,
POBr.sub.3, O.sub.2SBr.sub.2, (OCBr).sub.2 (thus, L is Br), and a
sulfonating agent, thus L is a sulfonyl ester, to provide the
corresponding 5-Bromo-2-(L)methyl-pyridine, preferably,
5-Bromo-2-(halo)methyl-pyridine, where "halo" is preferably Cl, Br,
and I. Although any of the above-mentioned L-derivatizing agents
are suitable for the process of the invention, it is preferable to
use thionyl chloride. It will be appreciated that other
L-derivatizing agents not specifically mentioned herein may also be
used in the process of the present invention. Any suitable solvent
system may be employed, preferably a solvent system comprising
non-protic solvents of moderate polarity, for example a mixture of
toluene and acetonitrile (MeCN). It is preferable to carry out the
reaction in a temperature range of from about 0.degree. C. to about
70.degree. C., more preferably from about 20.degree. C. to about
50.degree. C., more preferably at about 45.degree. C. Preferably
the initial concentration of the alcohol substrate is from about
0.5 M to about 0.9 M. Preferably, the chlorinating agent is used at
least in a 1.5-fold excess based on the alcohol substrate.
[0048] It is preferable to run the reaction until the alcohol has
been completely consumed. The reaction can be monitored for
complete conversion of the alcohol, for example, by HPLC or gas
chromatographic techniques. At the end of the reaction, optionally
the reaction mixture is quenched with an aqueous base. It is
particularly preferred to quench the reaction when it is being
carried out on a large scale. When a quench step is included in the
reaction, preferably, the reaction is quenched using a potassium
carbonate solution. Following completion of the reaction, the
organic layer of the reaction mixture is separated, washed and
concentrated.
[0049] Thus obtained, the concentrate is charged into a suitable
apparatus and combined with triorgano-phosphite compound having the
structure of Formula A, wherein R.sup.9 is selected independently
for each occurrence from alkyl, aryl heteroaryl and arylalkyl
groups having 1 to 10 carbon atoms. ##STR21##
[0050] Preferably, R.sup.9 is the same for all occurrences and is
alkyl, more preferably linear alkyl, more preferably ethyl.
[0051] The reaction mixture is heated and maintained at a
temperature to drive the reaction, preferably to a temperature of
from about 130.degree. C. to about 150.degree. C . After a
sufficient period of maintaining the reaction mixture at a suitable
temperatrue, preferably until complete conversion of the methyl-L
derivatized substrate (the compound 137D for example, when a
chlorinating L-derivatizing reagent is employed, a methylchloride
substrate) the reaction mixture is cooled and treated with
hydrochloric acid to convert the phosphonate (compound 138D) into
the corresponding hydrochloride salt (compound 139D). Preferably,
the temperature of the reaction mixture is maintained at less than
about 20.degree. C. during this treatment. Although HCl treatment
can be carried out using any conventional means, for example, by
bubbling HCl gas through the reaction mixture, or treating the
mixture with an HCl solution, it is convenient to treat the
reaction mixture by stirring it with an HCl solution, preferably an
HCl/isopropanol solution.
[0052] After the salt is formed, it begins to precipitate from the
reaction mixture. Heptanes are added to complete the salt
precipitation and improve the yield of salt recovered from the
reaction mixture. It is preferred to keep the reaction mixture at a
temperature of less than about 20.degree. C. during this addition.
The phosphonate hydrohalide salt (compound 139D) is then recovered
from the reaction mixture by vacuum filtration, washed and vacuum
dried for use in the synthesis of compound 116.
[0053] In the last step of Scheme VI, compound 116 is synthesized
from the phosphonate hydrochloride salt by reacting it with a
3-fluorophenylboronate of the structure of the compound of Formula
B: ##STR22## where R.sup.11 is selected independently for each
occurrence from alkyl, aryl heteroaryl and arylalkyl groups having
1 to 10 carbon atoms and hydrogen.
[0054] Although it will be appreciated that any 3-fluorophenyl
boronate can be reacted with the
(5-halo-pyrid-2-yl)-methylphosphonate salt compound (139D), it is
preferred to use 3-fluoroboronic acid (thus R.sup.11 for each
occurrence is H). It is preferred to carry this reaction out in a
two phase reaction medium, one aqueous and one organic, preferably
isobutyl acetate. Accordingly, the reaction is carried out by
providing an aqueous boronic acid solution/slurried with a
supported palladium catalyst, for example, palladium supported on
carbon black, for example, Degussa 5% Pd/C type E 105 CA/W.
Conversion of the phosphonate hydrochloride salt (compound 139D)
can be followed by HPLC assay. It is preferred to maintain reaction
conditions until the HPLC analysis indicates complete conversion of
the starting phosphonate. It is preferred to maintain the reaction
mixture at a temperature of from about 70.degree. C. to about
80.degree. C. during the reaction. It is preferred to initiate the
reaction with the starting phosphonate (compound 139D) present at a
concentration of about 0.5 M to about 1.0 M, and use at least a
1.3-fold excess of the boronate reagent. Workup of the reaction
mixture includes removing excess boronic acid by adjusting the
mixture to a basic pH, preferably a pH of from about pH 11 to about
pH 13, separating the organic layer by splitting, and removing
process impurities by washing the batch with a 2% aqueous NaCl
solution, and concentrating the organic layer. During workup, it is
preferred to maintain the reaction mixture at a temperature of from
about 20.degree. C. to about 30.degree. C. Product, compound 116,
is obtained by anti-solvent precipitation, for example, by treating
the organic phase with a sufficient volume of heptanes until the
product precipitates from solution.
[0055] With reference to Scheme IV, it will be appreciated that the
intermediate compounds of Formula 116 can be prepared by reacting
intermediate compounds of Formula 139d with other organometallic
reactants in place of boronates, for example, but not limited to:
fluoroaryl-alkylboranes; fluoroaryl-haloboranes; fluoroaryl- zinc,
-aluminium, -magnesium, and -tin reagents, and other organometallic
reagents represented by formula ##STR23## where "M" is an
organometallic reagent capable of displacing the X.sup.2 halogen of
compound 138 with a 3-fluoroaryl moiety.
[0056] The starting alcohol, 5-bromo-2-hydroxymethyl-pyridine,
compound 136, may be prepared from
5-bromo-2methyl-pyridine-N-oxide. This synthesis is disclosed in
detail in the copending '324 application, which is incorporated
herein in its entirety by reference. It will be appreciated that
the present invention process can be carried out using variously
substituted hydroxymethyl pyridines, as well as
5-bromo-2hydroxymethyl-pyridine obtained by any other means.
[0057] There follows an example preparation of
[5-(3-Fluoro-phenyl)-pyridin-2-ylmethyl]-phosphonic acid diethyl
ester (compound 16) which illustrates, but in no way limits, the
present invention.
EXAMPLE
[0058] The following solvents and reagents may be referred to by
their abbreviations in parenthesis: [0059] ethyl acetates: EtOAc
[0060] methanol: MeOH [0061] isopropanol: IPA [0062]
tertiarybutyl-methyl ether: TBMEsodium bistrimethylsilylamide:
NaHMDS [0063] triethyl amine: TEA [0064] trifluoro acetic acid: TFA
[0065] tertiary-butoxycarbonyl: t-BOC [0066] tetrahydrofuran: THF
[0067] lithium bis(trimethylsilyl)amide: LiHMDS [0068] mole: mol.
[0069] HPLC--high pressure liquid chromatography
Example 1
Preparation of [5-(3-Fluoro-phenyl)-pyridin-2-ylmethyl]-phosphonic
acid diethyl ester
[0070] ##STR24##
[0071] To a reaction vessel was charged (100 g, 0.29 mol) of
phosphonate compound 139 (where R.sup.9 is ethyl- for all
occurrences), 5% Pd/C 50% wet (5.0 g), 3-fluorophenylboronic acid
(61 g; 0.44 mol) and sodium carbonate (100 g; 0.94 mol). 600 ml of
iso-butyl acetate was charged and the mixture agitated. 400 ml of
water was charged, and the agitated mixture was heated to
70-80.degree. C. for at least 3 h at which time an HPLC assay
indicated complete reaction. Upon completion, the reaction mixture
was cooled to 25.degree. C. and filtered to remove the Pd/C
catalyst. The catalyst cake was washed with 200 ml iso-butyl
acetate (combined with the filtrate/batch) and 100 ml water
(waste). 25% sodium hydroxide solution was used to adjust batch to
pH 11-13. During the process the reaction mixture was maintained at
a temperature of from 20.degree. C. to 30.degree. C. The organic
layer was separated and washed with 500 ml water with agitation. A
25% sodium hydroxide solution was used to adjust the pH of the
batch to a pH value of from pH 11 to pH13. Throughout the was the
temperature was maintained at a value of from about 20.degree. C.
to about 30.degree. C.
[0072] After washing the layers were separated and the organic
layer was washed with 300 ml of 2% sodium chloride solution with
10-15 minutes with agitation. The layers were separated and an HPLC
assay of the organic layer indicated impurities were reduced to a
desirable level. Darco (10 g) was added to the organic layer. The
resultant slurry was agitated for 1 hour, and then filtered to
remove the de-coloring agent. The filter cake was washed with 200
ml iso-butyl acetate (combined with the filtrate/batch) and the
batch was concentrated under reduced pressure to about 200 ml at
from 40.degree. C. to 50.degree. C., then cooled to a temperature
of from 15.degree. C. to 25.degree. C. Heptanes (1000 ml) were
charged into the cold concentrate over 2.5-3 hr, maintaining the
temperature at from about 15.degree. C. to 25.degree. C. The
mixture was cooled to a temperature of from -15.degree. C. to
-5.degree. C. over 3 hr and agitated at the same temperature for 1
hr. The crystalline solid was filtered, washed with 200 ml
heptanes, and dried overnight under vacuum at a temperature of from
about 25.degree. C. to 35.degree. C. to provide 70.37 g (75%). Mp
61-63.degree. C. .sup.1H NMR (CDCl.sub.3) .delta. 1.3 (t, J=7.05
Hz, 6H), 3.47 (d, J=22.02 Hz, 2H), 4.12 (q, J=7.08 Hz, 4H), 7.10
(ddd, J=8.42, 2.55, 0.88, Hz, 1H), 7.28 (ddd, J=9.85, 2.36, 1.80
Hz, 1 H), 7.36 (dt, J=7.86, 1.27, Hz, 1H), 7.46 (m, 1H), 7.83 (ddd,
J=8.1, 2.2, 0.32 Hz, 1H), 8.76 (d, J=2.38, 1H).
Example 1A
Preparation of [(5-Bromo-Pyridin-2-ylMethyl)-Phosphonic Acid
Diethyl Ester] Hydrochloride
[0073] ##STR25##
[0074] Into a solution of 5-bromo-2-hydroxymethyl-pyridine (BHMP,
50.0 g, 266 mmol) in toluene (100 mL) and MeCN (150 mL) was added
thionyl chloride (35.0 mL, 57.1 g, 479 mmol). This reaction mixture
was stirred at 45.degree. C. for 4 hours. Toluene (250 mL) was
added to the reaction mixture and the reaction mixture was cooled
to 0.degree. C. The reaction was quenched with 20% potassium
carbonate solution (450 ml), keeping the temperature below
30.degree. C. The reaction mixture was stirred for 10 min and the
layers were partitioned. The organic layer was washed once with
water (100 mL) and the organic layer was concentrated under reduced
pressure to a volume of about 200 mL. The concentrated crude
solution was transferred to a distillation apparatus. At room
temperature, triethyl phosphite (200 mL, 1144 mmol) was added to
the crude concentrated solution and the reaction mixture was heated
to 145.degree. C. until reaction was completed. Distillate driven
off of the reaction mixture during the heating period was collected
(.about.200 mL). After 12 hours of heating the reaction mixture was
cooled to 0.degree. C. A solution of 5-6N HCl in isopropanol (150
mL) was slowly added to the cooled reaction mixture over a period
of 1 hour, keeping the internal temperature below 5.degree. C.
Heptanes (350 mL) were then added to the mixture over 1 hours and
the resultant slurry was stirred for another hour. The solid
product was collected by vacuum filtration, washed with 10%
IPA/heptanes and dried under vacuum at room temperature to provide
81 g of product (89%). Mp. 118-120.degree. C. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 1.29 (t, J=7.05 Hz, 6H), 3.88 (d, J=22.3 Hz,
2H), 4.19 (m, 4H), 7.88 (dd, J=8.57 Hz, 1H), 8.34 (dd, J=8.55, 2.18
Hz, 1H), 8.71 (s, 1H).
Preparation of Starting Material:
5-bromo-2-hydroxymethylpyridine
[0075] The starting alcohol (5-bromo-2hydroxymethylpyridine) used
above in Example 1 was prepared in two steps. Step I ##STR26##
[0076] To a solution of 5-bromo-2-methylpyridine N-oxide (10.0 g,
5.32 mmol) in EtOAc (50.0 ml) at 0.degree. C. was added dropwise
trifluoroacetic anhydride (9.8 ml, 6.92 mmol.) while keeping the
temperature below 50.degree. C. After the completion of the
addition, the mixture was heated to a temperature of from
75.degree. C. to 80.degree. C. and stirred for at least 1 h. An
HPLC assay of the mixture indicated the reaction was complete when
5-bromo-2-methylpyridine N-oxide was present a less than 5% of its
initial value.
[0077] Upon completion, the mixture was cooled below 50.degree. C.
and MeOH (10.0 ml) was added. The mixture was heated for at least 1
h at 50.degree. C. The solution was concentrated under vacuum and
MeOH was removed by displacement with EtOAc (40.0 ml) and
concentrated to a volume of 30 ml. To the concentrate was added
toluene (20.0 ml) and the solution cooled to -10.degree. C. over 2
h. The crystalline solid was filtered and washed with cold toluene
and dried overnight under vacuum at 35.degree. C. to provide 10.1 g
(63%) of product. Mp 89-92.degree. C. .sup.1H NMR (DMSO-d.sub.6)
.delta. 4.56 (s, 2 H), 7.49 (d, 1 H), 8.1 (dd, J=2.3, 2.3 Hz, 1 H),
8.64 (d, J=2.1Hz, 1H). Step II ##STR27## A slurry of compound 36
(10.0 g, 33.1 mmol) in TBME (100 ml) was treated with 20% potassium
carbonate (20 ml) solution and stirred at room temperature for 1 h.
The layers were separated and the organic layer was washed with
water. The solution thus obtained was concentrated to .about.10 mL
volume and 20 mL heptanes was added at 45-50 C. Solution was cooled
to 20-25 C and additional 20 mL heptanes was charged. Reaction was
agitated at 20-25 C for 2 hours and filtered. Product was dried
overnight under vacuum at 15-25 C to give 5.0 g (80%) of product.
.sup.1H NMR (CDCl.sub.3) .delta. 3.36 (bs, Hz, 1 --OH), 4.75 (d,
J=9.07 Hz, 2H), 7.21 (d, J=8.31 Hz, 1H), 7.83 (d, J=8.28 Hz, 1H),
8.64 (d, J=1.89 Hz, 1H).
[0078] The above description of the invention is intended to be
illustrative and not limiting. Various changes or modifications in
the embodiments described herein may occur to those skilled in the
art. These changes can be made without departing from the scope or
spirit of the invention
* * * * *